The progression of cancer from benign primary tumors to malignant metastatic lesions is achieved through intricate interplay of diverse signaling pathways. One of these pathways, Hippo, is particularly interesting because it has been shown to function both in tumor suppression and in tumor formation based upon context. The mechanisms that orchestrate these opposing roles in cancer remain unknown. In preliminary experiments, I have discovered that YAP, a transcription co-activator and key downstream effector of the Hippo pathway, is highly expressed and nuclear in the basal cells of benign papilloma tumors of the skin. In striking contrast, YAP becomes cytoplasmic in the basal cells of malignant squamous cell carcinomas (SCCs). Since it is the basal cells of both papillomas and SCCs that possess the proliferative, tumor-initiating potential, this suggests that if YAP functions in malignant progression, either its loss from the nucleus or its gain in the cytoplasm must be critical. In this proposal, I aim to 1) Determine the biological importance of YAP in epidermal homeostasis, papilloma formation and SCC development, 2) Probe the role of nuclear YAP in papilloma formation, 3) Elucidate YAP/TEAD targets in papillomas, 4) Identify which targets are critical to skin tumorigenesis and 5) Decipher upstream regulator(s) responsible for YAP localization in papilloma versus SCC, and establish their physiological relevance. Through this study, I hope to reveal how YAP functions in skin homeostasis and malignancy, and shed light on current paradoxes regarding YAP's roles in cancer.